This is a competitive renewal application of our currently funded Program Project (P01) award entitled ?Age- induced Impairment of Nutrient Signaling Results in Bone Loss?. Osteoporosis is a major public health problem affecting 44 million Americans. The estimated annual direct health-care cost for osteoporosis totaled $17 billion in 2001 and is rapidly rising. A critical barrier to correcting the problem of frailty and osteoporosis is a poor understanding of how nutrient-related stimuli and epigenetic mechanisms interact to induce bone and muscle loss. Our central hypothesis is that aging alters epigenetic regulatory systems (e.g., miRNA, acetylation) that act through nutrient signaling pathways on stem cells to affect musculoskeletal function. This project will improve scientific knowledge, technical capability, and clinical practice as they relate to age-induced muscle and bone loss by 1) defining specific epigenetic mechanisms that lead to bone and muscle loss with aging and 2) identifying specific nutritional interventions that can reduce or reverse these age-related changes. This is a highly integrated proposal from a group with an established track record of interactions, productivity and collaborations. Four individual projects, focused on epigenetic regulation and nutrient-related stimuli, comprise this application. The proposal also includes three Core facilities that will provide essential support to the Projects: an Administrative Core (Core A) that includes biostatistics and bioinformatics; a Bone Biology Core (Core B), which will provide the bone-specific techniques utilized by all the investigators; and a Bone Stem Cell Core (Core C) that will provide bone-derived cells to all investigators, including mouse and human bone marrow progenitor cells. The project has three specific aims: Aim 1 will test the hypothesis that age-related changes in epigenetic signals alter musculoskeletal stem cell function; Aim 2 will test the hypothesis that specific dietary interventions (e.g., selective amino acid supplementation or intermittent fasting/protein feeding) can reverse age-related changes in epigenetic modifications and promote normal stem cell function; Aim 3 will test the hypothesis that relevant age-related epigenetic modifications identified in our mouse model are translatable to normal human physiology. The long-term impact of this project will be new findings on the epigenetic mechanisms underlying bone and muscle loss with age, and new countermeasures for reducing or reversing musculoskeletal aging.